Bases genético-moleculares de la Hipertensión Arterial Pulmonar, su expresión fenotípica en la población española y su papel en formas poco frecuentes de Hipertensión Arterial Pulmonar

Abstract

Pulmonary Arterial Hypertension is a rare and severe condition, characterized by progressive obliteration of small-resistance pulmonary arteries and arterioles. This rise in pulmonary vascular pressure and resistance results in right heart failure and death. In the last two decades, knowledge of hereditary predisposition to PAH has drastically increased. Genes described in PAH are associated with a great variety of molecular pathways. To date, 12 genes have been associated with PAH with a high level of evidence, and 5 have been associated with alow level of evidence. Furthermore, high-throughput sequencing (HTS) technologies have led to the identification of novel associated genes. The main gene involved in PAH encodes the bone morphogenic protein receptor type 2 (BMPR2), a receptor belonging to the transforming growth factor beta (TGF-β) superfamily. Other genes have also been identified: potassium channel genes(KCNK3, KCNA5, ABCC8), T-box transcription factor 4 (TBX4), and other genes in the TGF-β/BMP signaling pathway (BMP9/GDF2, SMAD1, SMAD4, SMAD9, BMPR1B). Also, there is increasing evidence for the involvement of other genes in PAH with less frequency and in different pathways. More recently, a “second hit” hypothesis came up due to the identification of two pathogenic variants in two genes related to PAH. This makes necessary novel approaches using Next Generation Sequencing (NGS) to obtain information from a set of genes, the entire exome or even the whole genome...